Epidermal growth factor receptor (EGFR) inhibition has been proven to be effective in an experimental nephritis models. However, Omachiet al showed that treatment with erlotinib, EGFR inhibitor, suppressed renal inflammatory cytokine expression but did not show significant positive effects on AS renal pathology in X-linked AS mice. This lack of effect may suggest that other signalling pathways besides EGFR are seminal in AS. Moreover, EGFR inhibitors usually have an unacceptable safety profile [2, 14].
The combination of paricalcitol, a ‘selective’ vitamin D receptor activator, and ACEIs may delay progressive renal fibrosis and renal failure due to a synergistic effect. However, to date there is not enough evidence in humans to fully recommend its use in AS patients [2, 15].
Lipotoxicity may contribute to the pathogenesis of glomerular diseases. In AS mice, hydroxypropyl-b-cyclodextrin protects AS mice against the development of proteinuria, progressive renal failure and fibrosis, and improves survival. In adult patients with AS and incident hypercholesterolemia, statins might be an additional treatment option to delay renal failure and prevent cardiovascular events .
In AS, around 50% of mutations are missense mutations. In many of these cases an abnormal protein is secreted but does not pass the quality control of the endoplasmic reticulum (ER) which degrades or retains the misfolded chains. This is accomplished through the unfolded protein response (UPR) pathway, which is activated by the ER stress. Chaperones have been proven to be effective in several diseases and there is already a commercial chaperone for an inherited kidney disease: migalastat for Fabry disease. In AS, a chaperone could promote triple-helix formation and consequently allow misfolded collagen IV proteins to reach their destination and function suboptimally but nevertheless sufficiently well to grant a resistant GBM . Treatment of cells expressing mutant laminin β2 (LAMB2) gene with the chemical chaperone taurodeoxycholic acid (TUDCA) can facilitate protein folding and trafficking, and increase the secretion of the mutant LAMB2 protein . A charoperone, sodium 4-phenylbutyrate increases collagen IV α5 mRNA levels, reduces ER stress and autophagy, and possibly facilitates collagen IV α5 extracellular transport .
The rationale of stem cell-based therapy in AS is that these cells isolated from healthy donors will migrate and engraft in renal glomeruli, where they may differentiate into functional podocytes, producing a new functional GBM to prolong kidney function. Moschidou et al found that human first trimester foetal chorionic stem cells are able to migrate to glomeruli and to differentiate down the podocyte lineage in vitro and in vivo, with a delay in progression of renal pathology due to a combination of anti-inflammatory effects and replacement of the defective resident podocytes in mice. Bone marrow transplantation (BMT) has been studied in mice models of AS but unfortunately, itis a very aggressive procedure usually performed in life-threatening diseases. The uncertainties in the studies of BMT in mouse models of AS prevent the use of this treatment in AS patient [2, 18].
Other treatment options including CRISP/Cas9 genome editing, empaglifozin, pentraxin-2, STAT3 inhibition, LOXL2 inhibition and DDR1 inhibition also showed promising results in treating AS.